Chronic alcohol abuse predisposes to bone fractures but why this happens is unclear. Nutritional and hormonal deficiencies have been postulated to increase fracture risk but studies comparing alcoholics to healthy controls have often not shown significant differences. Thus, other factors are likely involved. A critical feature of bone homeostasis is the need for continual differentiation of stem cells to osteoblasts, the cells responsible for new bone formation. Single gene diseases that impact bone integrity can shed light on novel factors that regulate stem cell differentiation to osteoblasts. Recently, gene mutations that result in complete absence of pigment epithelium-derived factor (PEDF) have been identified as the cause of Osteogenesis Imperfecta (OI) Type VI, an autosomal recessive disease characterized by severely weakened bone and early fractures. We previously published that PEDF KO mice recapitulate the human OI Type VI phenotype with marked trabecular bone loss in young mice. We further showed that PEDF directs a key signaling pathway that is responsible for stem cell differentiation to osteoblasts and away from adipocytes. Based on this human disease, we have defined PEDF as a novel osteoblast differentiation factor. The studies outlined in this application will investigate whether PEDF can rescue the bone loss that occurs in two well-characterized models of alcohol feeding. We will also investigate the signaling pathways that mediate new osteoblast formation. Finally, we have collaborations with clinicians who have OI Type V and VI patients. Inducible pluripotent stem cells will be created from these patients. We will then assess whether these PEDF-null stem cells can differentiate normally to bone cells. Findings from this application may be helpful in defining molecules that can mimic PEDF's actions on bone cell differentiation.